The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's election with traverse of Group I, to cancer, granzyme B, in the reply filed on June 8, 2026 is acknowledged. The traversal is on the ground(s) that the office has not shown that a serious burden would be required to examine all of the claims. See Applicants’ remarks p. 1-2. This is not found persuasive because the reasons are the same as noted on at least p. 3-5 of the restriction requirement, which note that each invention and species are distinct and impose a serious burden.
The requirement is still deemed proper and is therefore made FINAL.
Claims 14-23 have been withdrawn from further consideration by the examiner because they are drawn to non-elected inventions. Claims 1-13, to cancer, Granzyme B, are under consideration.
Priority: This application is a CON of U.S. Application 16859881, filed April 27, 2020, now U.S. Patent 12338483, which claims benefit to provisional application 62/811619, filed February 28, 2019.
Claim Objections
Claim 1 is objected to because of the following informalities: in claim 1, the language should be consistent when reciting the sensor, whether it is protease activity sensor or protease sensor. Additionally claim 1, line 7, appears to have an indentation between “substrate” and “and” which is not believed to be necessary. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 and the dependent claims are drawn to a method for determining protease activity in a biological sample, comprising: providing the biological sample with a protease activity sensor comprising a first protease substrate and a second protease substrate; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, and wherein the protease activity sensor provides a detectable signal when both the first substrate and the second substrate are cleaved; detecting the presence of the detectable signal in the sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the sample.
The components and/or elements of the sensor are defined through their activities only and do not require any particular structure. The recited genera of protease substrates, proteases, protease sensors, reporter molecules are defined through their activity only and do not require any particular structure.
The specification discloses a representative species of a sensor that sense the specific proteases Granzyme B (Gzm B) and thrombin (Thrb), where the sensor is designed to emit fluorescent reporters (5-FAM) after cleavage of both protease substrates (at least example 1). Other than the representative species of the specific protease sensors, the specification fails to disclose any other protease substrates, proteases, protease sensors, reporter molecules, and combinations thereof, all being unlimited in structure. The skilled artisan cannot necessarily envision the detailed structures of ALL the variant protease enzymes, substrates, protease sensors, reporter molecules, and combinations thereof, all having no particular structure, that successfully detect and/or identify any protease activity in any biological sample because the specification provides no guidance as to which structural features are essential and critical to have and form protease sensors comprising which protease substrates and are recognized by which proteases, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the methods of making the claimed invention. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating or making it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Rajopadhye et al. (US 9999687). Rajopadhye et al. teach imaging agents comprising an enzymatically cleavable oligopeptide linked to either two fluorophores or one fluorophore and one quencher, where the agent is activated by proteases (at least col. 1 lines 19-61). Rajopadhye et al. teach providing an in vitro method comprising contacting a biological sample with any one or more of the imaging agents; allowing the agent to bind to or associate with a biological target; and detecting a signal emitted from the fluorophore to determine whether the agent has been activated by or bound to the biological target (at least col. 5 lines 57-64). Rajopadhye et al. teach an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to one or more proteases, at least one fluorophore is no longer quenched by the other (at least col. 6 lines 53-58). Rajopadhye et al. teach the enzymatically cleavable oligopeptide is cleavable by at least one enzyme selected from among metalloproteases, serine proteases, etc. (at least col. 45 lines 4-14). Therefore, Rajopadhye et al. can be deemed to anticipate instant claims 1-5.
Regarding instant claims 6-7, Rajopadhye et al. teach the agents can also be chemically linked to nanoparticles (at least col. 25 lines 41-47). Regarding instant claim 8, Rajopadhye et al. teach the agents can include the nanoparticle with a polymer coating suitable for attaching a plurality of agents (at least col. 25 lines 48-54).
Regarding instant claims 9-11, Rajopadhye et al. teach the methods and compositions comprising the agents can be used to help a physician or surgeon identify and characterize areas of disease (at least col. 68 lines 33-45), including cancer (at least col. 68 line 62).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 12 are rejected under 35 U.S.C. 103 as being unpatentable over Rajopadhye et al. (US 9999687) in view of Shu et al. (WO 2015154006). The teachings of Rajopadhye et al. over at least instant claim 1 is noted above. Rajopadhye et al. disclose the methods and compositions comprising the agents can be used to help a physician or surgeon identify and characterize areas of disease (at least col. 68 lines 33-45). Rajopadhye et al. do not explicitly teach that the one or more proteases (first protease and/or second protease) are promoted by a therapeutic agent.
Shu et al. disclose fluorescent protease reporters (abstract). Shu et al. disclose the activity of a protease can be promoted by a therapeutic agent (at least paragraph 0026).
Regarding instant claim 12, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a therapeutic agent in the biological sample disclosed in the method of Rajopadhye et al. for detecting or determining protease activity in sample because Shu et al. disclose protease activity can be detected after administration of a therapeutic agent.
Claims 1-4, 6-11, 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kwong et al. (WO 2018064383). Kwong et al. disclose an activity-based nanosensor composition for detecting protease activity comprising a cleavable detectable substrate (abstract). Kwong et al. disclose the compositions can be used to detect proteolytic activity of proteases associated with T cell cytotoxicity (in patients being treated with cancer immune therapies); these proteases include but are not limited to T cell proteases, including Granzyme B, Granzyme A, etc. (at least p. 17 lines 10-27). Kwong et al. disclose that in order to detect proteolytic activity, the compositions can be designed to contain one or more detectable peptide sequences (peptide substrates) that are recognized by proteases and are also linked or coupled to scaffolds, such as nanoparticles, and the detectable peptide sequence can accumulate in a bodily fluid after being cleaved from the peptide-scaffold complex by the protease of interest (at least p. 17 lines 28 to p. 18 line 5). Kwong et al. disclose a conjugate comprising one or more peptides sequences operably linked to at least one scaffold, wherein the conjugate can be recognized by a protease; in some embodiments, the one or more peptide sequences and/or the scaffold of the conjugate can be capable of generating a detectable signal; in some embodiments, the one or more detectable peptide sequences can comprise a reporter and a protease cleavage/recognition site (at least p. 18 lines 8-14), where when the composition or conjugate is exposed to enzymes, for instance, proteases, the at least one detectable peptide sequence can be cleaved, such that the reporter of the detectable peptide sequence released; the reporter can be detected locally at the site of the cleavage or in the subjects blood or plasma (at least p. 18 lines 15-18); the reporter thus functions as a “messenger” of enzyme activity (at least p. 18 lines 20-22).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed method for determining protease activity in a biological sample, comprising: providing the biological sample with a protease activity sensor comprising a first protease substrate and a second protease substrate; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, and wherein the protease sensor provides a detectable signal when both the first substrate and the second substrate are cleaved; detecting the presence of the detectable signal in the sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the sample (instant claim 1) in view of the teachings of Kwong et al. The motivation to do is provided by the prior art. Kwong et al. disclose designing a protease activity sensor comprising at least one protease substrate and a reporter, which therefore includes a first protease substrate and a second protease substrate, where the protease activity sensor provides a detectable signal when the at least one protease substrates are cleaved by the proteases of interest and the enzymatic activity of the protease enzymes are identified, where the it is further disclosed that the detectable peptide sequences are present in bodily fluids (see above). Therefore, it would have been obvious to arrive at the claimed method because Kwong et al. disclose protease activity sensors comprising the same features recited and used for the same purpose recited, i.e. a method for determining protease activity in a biological sample.
Regarding instant claims 2-3, Kwong et al. disclose in some embodiments, the one or more peptide sequences and/or the scaffold of the conjugate can be capable of generating a detectable signal; in some embodiments, the one or more detectable peptide sequences can comprise a reporter and a protease cleavage/recognition site (at least p. 18 lines 8-14); the reporter includes for example, a fluorophore (at least p. 18 lines 22-23).
Regarding instant claim 4, Kwong et al. disclose in the presence of a protease, i.e. GzmB, peptide substrates are cleaved and fluorescent reporters are released into solution, increasing sample fluorescence (at least 7 lines 3-6, also Fig. 2A); where increases in fluorescent intensity were observed only in samples containing recombinant Gzm (at least p. 71 lines 10-11). Therefore, Kwong et al. can be deemed to disclose first and second peptide substrates conjugated to a fluorescent quencher where cleavage of the first and second peptide substrates permits an increase in fluorescence (or the fluorescent molecule to provide a detectable signal).
Regarding instant claims 6-7, as noted above, Kwong et al. disclose that in order to detect proteolytic activity, the compositions can be designed to contain one or more detectable peptide sequences (peptide substrates) that are recognized by proteases and are also linked or coupled to scaffolds, such as nanoparticles (at least p. 17 lines 28 to p. 18 line 5).
Regarding instant claim 8, Kwong et al. disclose a plurality of protease activity sensors are bound to the nanoparticle (at least 7 lines 3-6, also Fig. 2A).
Regarding instant claims 9-11, 13, as noted above, Kwong et al. disclose the compositions can be used to detect proteolytic activity of proteases associated with T cell cytotoxicity (in patients being treated with cancer immune therapies); these proteases include but are not limited to T cell proteases, including Granzyme B, Granzyme A, etc. (at least p. 17 lines 10-27).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12338483 (‘483). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘483 patent claims are drawn to a method for determining protease activity in a biological sample, comprising: providing or contacting the biological sample with a protease activity sensor comprising a first protease substrate and a second protease substrate; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, and wherein the protease activity sensor provides a detectable signal when both the first substrate and the second substrate are cleaved; detecting the presence of the detectable signal in the sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the sample. Further, the component and features recited in the instant dependent claims are also all recited in the ‘483 patent claims.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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